The present invention relates to methods of preparation of homocamptothecins and intermediates therefor and, particularly, to methods and intermediates for the enantioselective synthesis (20R)-homocamptothecins.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
In general, camptothecins and homocamptothecins as illustrated in FIG. 1 (sometimes referred to generally herein as camptothecins or the camptothecin family) are DNA topoisomerase I inhibitors useful, for example, as anticancer drugs. Analogs of the natural product camptothecin frequently have one or more substituents in place of hydrogen in the A and/or B rings at carbons 7, 9, 10, and/or 11. These analogs are among the most important classes of compounds available for treatment of solid tumors. Topotecan (tpt) and CPT-11 were the first two members in the camptothecin family to gain United States Food and Drug Administration full approval status (topotecan in 1996 as second-line therapy for advanced epithelial ovarian cancer, topotecan again in 1998 for the treatment of small cell lung cancer, CPT-11 in 1998 as first-line therapy for colon cancer).
Recently, Lavergne et al. have shown that expansion of the E-ring of camptothecin to produce a homocamptothecin (hcpt) enhances the solution stability of camptothecin while maintaining anticancer activity. U.S. Pat. No. 5,981,542; PCT International Patent Application No. PCT/FR00/00461; Lavergne, O., et al., J. Med. Chem., 41, 5410-5419 (1998); and Lavergne, O., et al., Bioorg. Med. Chem. Lett., 7, 2235-2238 (1997). Once again, many of the most important compounds in this class have one or more substituents on rings A and/or B. For example, 10,11-difluorohomocamptothecin is in early stage clinical trials.
7-Silyl camptothecins and 7-silyl homocamptothecins (sometimes referred to as silatecans and homosilatecans) are important classes of lipophilic camptothecin and homocamptothecin analogs, See, for example, a) Josien, H., et al., Bioorg. Med. Chem. Lett., 7, 3189 (1997); b) Pollack, I. F.; et al., Cancer Research, 59, 4898 (1999); Bom, D., et al., Clinical Cancer Research, 5, 560 (1999); Bom, D., et al., J. Med. Chem., 42, 3018 (1999).
Many of the most interesting silatecans and homosilatecans contain one or more additional substituents (for example, hydroxy or amino) in the A ring, and the combination of these substituents can provide significant improvements over either of the corresponding mono-substituted analogs. For example, DB-67, or 7-tert-butyldimethylsilyl-10-hydroxycamptothecin, is highly active against cancer cells and tumors and possesses many favorable physical and pharmacological properties. Silatecans and homosilatecans in general show a number of attractive features including high activity against a broad spectrum of solid tumors, low binding to blood proteins, resistance to lactone opening, high lipophilicity, and potential oral availability among others.
Camptothecins, silatecans, homocamptothecins and homosilatecans (referred to herein generally as xe2x80x9ccamptothecinsxe2x80x9d and xe2x80x9chomocamptothecinsxe2x80x9d) have been prepared using cascade radical annulation routes. See, for example, U.S. Pat. Nos. 6,136,978, 6,150,343, 6,207,832 and 6,211,371, Curran, D. P, et al., Angew. Chem., Int. Ed. Eng., 34, 2683 (1995) and Josien, H., et al., Chem. Eur. J., 4, 67 (1998). Those total synthetic routes are highly flexible and allow the preparation of a diverse array of, for example, silatecan and homosilatecan analogs by both traditional and parallel routes. In that regard, substantially any substituent can be placed on, for example, the A- or B-ring of the camptothecin structure using those synthetic routes.
The cascade radical annulation route to homocamptothecins and homosilatecans is summarized in FIG. 2a. The key iodopyridone 12 is first N-propargylated with a propargyl bromide 13 and the resulting intermediate 14 is next reacted with an aryl isonitrile 15 under the conditions of cascade radical annulation. The substituent on the propargyl bromide (RB) becomes the B-ring substituent at C7 while the substituent(s) on the isonitrile (RA) become(s) the A-ring substituents. In this way, many different homocamptothecins and homosilatecans 16 can be made from a single key intermediate 12. In turn, 12 is made from 10a by the steps of iododesilylation and demethylation.
In the Lavergne route to homocamptothecins (FIG. 2b), compound 11 is alkylated with a bromomethyl quinoline 17 followed by Heck type cyclization. Accordingly, compounds of the structures 10-12 and their relatives are crucial intermediates in the synthesis of homocamptothecins, homosilatecans, and analogs.
Unfortunately, current syntheses of compounds 10-12 are racemic synthesis, requiring subsequent resolution of the active enantiomer. These resolutions add extra steps and are wasteful because the undesired enantiomer (50% of the mixture) must be discarded.
It is thus very desirable to develop enantioselective synthetic routes and intermediate compounds for use therein for the synthesis of biologically active (20R)-homocamptothecins.
In one aspect, the present invention provides generally methods of synthesis of compounds of the formula: 
from readily available compounds of the formula (IV): 
wherein R1 is, for example, hydrogen, fluorine, chlorine or SiR5R6R7 wherein R5, R6, and R7 are independently the same or different an alkyl group (preferably a lower alkyl group) or an aryl group. R2 is an alkyl group (preferably, a lower alkyl group). R3 is a protecting group (for example, acetate, methoxymethyl or tert-butyldimethylsilyl). R4 is an alkyl group (preferably, a lower alkyl group), an allyl group, a propargyl group or a benzyl group. X4 is H, Cl, Br or I.
Preferred embodiments of the compound of formula (I) for use in the synthetic methods of the present invention include those in which R1 is H or a trimethylsilyl group, R2 is a lower alkyl group, R3 is a methoxymethyl group, and R4 is an ethyl group.
In one embodiment, a nucleophilic organometallic species of the formula (IVa): 
is produced by converting X4 of the compound of formula (IV) to a metal or a metal-containing group X5 (referred to herein collectively as a xe2x80x9cmetal-containing groupxe2x80x9dxe2x80x94for example Li, CuCN, MgBr or MgI). The nucleophilic organometallic species is generated either by deprotonation (in the case that X4 is H) or halogen metal exchange (in the case that X4 is Cl, Br or I). If desirable, the initial metal-containing group can be exchanged for another by transmetallation. Preferred metals for metalation or transmetalation to generate nucleophiles have a Pauling electronegativity less than or equal to about 1.9, and more preferred metals have a Pauling electronegativity less than or equal to about 1.6. Examples of preferred metals include lithium, sodium, potassium, cesium, magnesium, titanium, chromium, zirconium, copper, and aluminum. Even more preferred metals are lithium, magnesium and copper.
The resultant nucleophilic species is reacted with a suitable electrophile to effect direct or indirect acylation to the compound of formula (I). One example of a direct acylation is the reaction of the nucleophile with an acid chloride R4C(O)Cl or with a so-called xe2x80x9cWeinrebxe2x80x9d amide having the formula R4C(O)N(Me)OMe. An example of an indirect acylation is the reaction of the nucleophile with an aldehyde having the formula R4CHO to effect hydroxyalkylation. The resultant alcohol is then oxidized to the compound of formula (I). Many methods for acylation of nucleophiles suitable for use in the present invention are known to those skilled in the art.
In another embodiment, the Stille coupling reaction is used to effect reaction of the compound of formula (IV) wherein X4 is Cl, Br or I with a compound having the formula R4C(O)SnR5R6R7, wherein R5, R6 and R7 are as defined above. Preferably, R5, R6 and R7 are independently the same or different a methyl group or a butyl group. The Stille coupling is often effected in the presence of a palladium catalyst with a ligand such as a triarylphosphine or triarylarsine. Many variants of the Stille procedure as known to those skilled in the art are suitable for use in the present invention.
In another aspect, the present invention also provides generally methods of synthesis of compounds of the formula: 
from compounds of the formula (I) by Wittig reaction, Peterson olefination, or one of the many others methods used by those skilled in the art for the conversion of ketones into alkenes. In the compounds of formula (II), R1, R2, R3, and R4 are as defined above, and R8 is xe2x80x94CHO, xe2x80x94CH2OH, xe2x80x94CH2OR9, wherein R9 is a protecting group, xe2x80x94CO2H, or xe2x80x94CO2R10 wherein R10 is an alkyl group (preferably a lower alkyl group) or an aryl group.
Preferred embodiments of the compound of formula (II) for use in the synthetic methods of the present invention include those in which R1 is H or a trimethylsilyl group, R2 is a lower alkyl group, R3 is a methoxymethyl group, R4 is an ethyl group, and R8 is CH2OH, CHO, CO2Me or CO2Et.
In another aspect, the present invention provides a method for direct conversion of the compounds of formula (IV) to the compounds of formula (II). In general, the compounds of formula (IV), wherein X is Cl, Br or I, are reacted under Stille reaction conditions as discussed above with compounds having the formula R4(R7R6R5)SnCxe2x95x90CHR8.
In a further aspect, the present invention provides a method for conversion of compounds of formula (H) to compounds of the formula: 
via asymmetric hydroxylation or asymmetric epoxidation. In the compounds of formula (III), R1, R2, R3, R4 and R8 are as defined above. In the compounds of formula (III), X1 is OH, X2 is H or OH, or together X1 and X2 are O (that is, an oxirane or epoxide). These compounds can further be converted to compound in which together X1 and X2 are OS(O)O (that is, a cyclic sulfite) or OS(O2)O (that is, a cyclic sulfate) as described below.
Preferred embodiments of the compound of formula (III) for use in the synthetic methods of the present invention include those in which R1 is H or a trimethylsilyl group, R2 is a lower alkyl group, R3 is a methoxymethyl group, R4 is an ethyl group, R8 is CH2OH, CHO, CO2H, CO2R10, wherein R10 is as described above, X1 is OH, X2 is H, or X1 and X2 together are O.
Preferred methods of asymmetric epoxidation provide compounds of formula (III) wherein X1 and X2 together are O (epoxide or oxirane) and include the Sharpless asymmetric epoxidation, the Jacobsen asymmetric epoxidation or the Jacobsen-Katsuki asymmetric epoxidation. An example of a preferred method of asymmetric epoxidation is the Sharpless asymmetric epoxidation wherein R8 is (E)xe2x80x94CH2OH.
Asymmetric dihydroxylation provides compounds of formula (III) wherein X1 and X2 are OH. A preferred method of asymmetric dihydroxylation is the Sharpless asymmetric dihydroxylation (AD). Diols X1 and X2 are readily converted to cyclic sulfites (X1 and X2 together are OS(O)O) by standard sulfinylation reagents, for example SOCl2, and to cyclic sufates (X1 and X2 are OS(O2)O) by standard sulfonylating reagents, for example SO2Cl2. Compounds of formula (III) wherein X1 is OH and X2 is H can, for example, be made by reduction of epoxides, cyclic sulfites or cyclic sulfates wherein R8 is CHO or preferably CO2R10 by reduction with, for example, samarium iodide. Compounds of formula (III) wherein X1 is OH, X2 is H and R8=CH2OH can be made by reduction of epoxides, cyclic sulfites or cyclic sulfates by aluminum or boron hydrides. An example of a preferred reducing agent is lithium aluminum hydride. Compounds of formula (II) or (III) wherein R8 is CH2OH, CHO, or CO2R10 can be readily interconverted with each other by standard oxidation, reduction and functional group transformation reactions.
Other methods for selective removal of a secondary hydroxyl group of the compounds of formula (III) (X2 is OH) in the presence of a tertiary hydroxy group (X1 is OH) to give the compounds of formula (III) in which X2 is H and X1 is OH are well known to those skilled in the art. For example, in the case where R8 is CO2R10, the secondary alcohol can be selectivly activated as a tosylate, a mesylate or a similar leaving group. The leaving can then be reductively removed with, for example, samarium diiodide. Alternatively, the leaving group can be displaced with, for example, bromide, iodide or phenyl selenide, and the so-formed product can be reduced with, for example, tributyltin hydride or tris(trimethylsilylsilicon) hydride. For an illustrative example of this later process, see Curran, D. P. and Ko, S. B., J. Org. Chem., 59, 6139-6141 (1994), the disclosure of which is incorporated herein by reference.
In still a further aspect, the present invention provides a method for the conversion of the compounds of formula (III) wherein R1, R2 and R4 are as defined above, X1 is OH, X2 is H and R8 is CO2H or CO2R10 into compounds of the formula (V): 
by treatment or exposure of the compounds of formula (III) with organic or inorganic acids. Preferably, acids with a pKa of less than about 4 are used. More preferably, acids with a pKa of less than about 2 are used. An example of a preferred acid for the conversion is trifluoroacetic acid.
In a further aspect the present invention provides a method of synthesizing a compound having the formula: 
wherein R1 is hydrogen, fluorine, chlorine or SiR5R6R7, wherein R5, R6, and R7 are independently the same or different an alkyl group or an aryl group, R2 is an alkyl group, R3 is a protecting group, R4 is an alkyl group, an allyl group, a propargyl group or a benzyl group, R8 is xe2x80x94CHO, xe2x80x94CH2OH, xe2x80x94CH2OR9, wherein R9 is a protecting group xe2x80x94CO2H, or xe2x80x94CO2R10, wherein R10 is an alkyl group or an aryl group, and X1 is OH, X2 is H or OH, or X1 and X2 together are O, including the steps of:
a) converting the ketone of compound (I) to an alkene to synthesize a compound having the formula: 
b) asymmetrically hydroxylating compound (II) or asymmetrically epoxidating compound (II).
In a further aspect, the present invention provides a method of synthesizing a compound having the formula: 
wherein R1 is hydrogen, fluorine, chlorine or SiR5R6R7, wherein R5, R6, and R7 are independently the same or different an alkyl group or an aryl group, R2 is an alkyl group, R3 is a protecting group, R4 is an alkyl group, an allyl group, a propargyl group or a benzyl group, R8 is xe2x80x94CHO, xe2x80x94CH2OH, xe2x80x94CH2OR9, wherein R9 is a protecting group xe2x80x94CO2H, or xe2x80x94CO2R10, wherein R10 is an alkyl group or an aryl group, and X1 is OH, X2 is H or OH, or X1 and X2 together are O, including the steps of:
a) reacting a compound having the formula: 
xe2x80x83wherein X4 is Cl, Br or I, under Stille reaction conditions with a compound having the formula R4(R7R6R5)SnC=CHR8 to synthesize a compound having the formula: 
b) asymmetrically hydroxylating compound (II) or asymmetrically epoxidating compound (II).
In a further aspect, the present invention provides a method for increasing the enantiopurity of compounds of the general structure of formula (V). These compounds can be made as described above in enantioenriched form. The compounds of formula (V) can also be made in racemic form by the methods described in, for example, U.S. Pat. No. 5,981,542; PCT International Patent Application No. PCT/FR00/00461; U.S. Pat. Nos. 6,136,978, 6,150,343, 6,207,832 or 6,211,371, or by standard racemic applications of the asymmetric methods described herein (for example, replacement of the Sharpless asymmetric epoxidation with a standard peracid epoxidation).
Compounds of formula (V) that are racemic or of low enantiopurity (typically, 50% ee or less) are first dehydrated to compounds of formula (VI): 
wherein R1, R2 and R4 are as described above. A preferred dehydrating reagent is the Burgess reagent (methoxycarbonylsulfamoyltriethylammonium hydroxide). Compounds of formula (VI) can then be converted to compounds of formula (VII) 
wherein R1, R2 and R4 are as described above, and X1 and X3 are OH or together are O, via asymmetric dihydroxylation or asymmetric epoxidation. A preferred method for synthesis of compounds of formula (VII) wherein X1 and X3 are OH is the Sharpless asymmetric dihydroxylation. Compounds of formula (VII) wherein X1 and X3 are OH can be converted to compounds of formula (VII) wherein X1 and X3 are together cyclic sulfites or cyclic sulfates and from there to compounds of formula (V) by methods analogous to those described for compounds of formula (III). Compounds wherein X1 and X3 together are O can be converted to compounds of formula (V) by reduction with, for example, samarium dioidide.
In still another aspect, the invention provides a method for increasing the enantiopurity of a homocamptothecin (that is, homocamptothecin or a derivative of homocamptothecin bearing, for example, substituents in rings A and/or B) including the steps of a) dehydration of the C20 hydroxy group to give a C20-C20a alkene, b) Sharpless asymmetric dihydroxylation to give a C20, C20a diol, c) activation of the secondary hydroxy group on C20a, and d) reductive removal of the activated group. Step a generally follows the methods described for the compounds of formula (VI), whereas steps b through d follow the methods described for the compounds of formulas (III) and (VII).
The process of the present invention for increasing the enantiopurity of homocamptothecin has broad scope with respect to substituents on the A and B rings, and is generally applicable to the homocamptothecins (including homosilatecans) including substituents as described, for example, in U.S. Pat. No. 5,981,542; PCT International Patent Application No. PCT/FR00/00461; U.S. Pat. Nos. 6,136,978, 6,150,343, 6,207,832, 6,211,371 and/or elsewhere, whether prepared by total synthesis or semisynthesis. Those skilled in the art will recognize the protection of certain A and B ring substituents, for example hydroxyl and amino, may be needed during some or all of the steps of this method of the invention.
In another aspect, the present invention provides generally a compound having the formula (I): 
wherein R1 is, for example, fluorine, chlorine or SiR5R6R7 wherein R5, R6, and R7 are independently the same or different an alkyl group (preferably a lower alkyl group) or an aryl group. R2 is an alkyl group (preferably, a lower alkyl group). R3 is a protecting group (for example, acetate, methoxymethyl or tert-butyldimethylsilyl), and wherein R4 is an alkyl group (preferably, a lower alkyl group), an allyl group, a propargyl group or a benzyl group.
In another aspect, the present invention further provides a compound having the formula (II): 
wherein R1 is, for example, hydrogen, fluorine, chlorine or SiR5R6R7 wherein R5, R6, and R7 are independently the same or different an alkyl group (preferably a lower alkyl group) or an aryl group. R2 is an alkyl group (preferably, a lower alkyl group). R3 is a protecting group (for example, acetate, methoxymethyl or tert-butyldimethylsilyl). R4 is an alkyl group (preferably, a lower alkyl group), an allyl group, a propargyl group or a benzyl group. R8 is xe2x80x94CHO, xe2x80x94CH2OH, xe2x80x94CH2OR9, wherein R9 is a protecting group, xe2x80x94CO2H, or xe2x80x94CO2R10 wherein R10 is an alkyl group (preferably a lower alkyl group) or an aryl group. The alkene can have either the E or the Z geometry in compound of formula (II).
In a further aspect, the present invention provides a compound having the formula (III): 
wherein R1 is fluorine, chlorine or SiR5R6R7, wherein R5, R6, and R7 are independently the same or different an alkyl group or an aryl group, R2 is an alkyl group, R3 is a protecting group, R4 is an alkyl group, an allyl group, a propargyl group or a benzyl group, R8 is xe2x80x94CHO, xe2x80x94CH2OH, xe2x80x94CH2OR9, wherein R9 is a protecting group xe2x80x94CO2H, or xe2x80x94CO2R10, wherein R10 is an alkyl group or an aryl group, and X1 is OH, X2 is H or OH, or X1 and X2 together are O, OS(O)O or OS(O2)O.
In another aspect, the present invention provides a compound having the formula (III): 
R1 is hydrogen, fluorine, chlorine or SiR5R6R7, wherein R5, R6, and R7 are independently the same or different an alkyl group or an aryl group, R2 is an alkyl group, R3 is a protecting group, R4 is an alkyl group, an allyl group, a propargyl group or a benzyl group, R8 is xe2x80x94CHO, xe2x80x94CH2OH, xe2x80x94CH2OR9, wherein R9 is a protecting group xe2x80x94CO2H, or xe2x80x94CO2R10, wherein R10 is an alkyl group or an aryl group, and X1 is OH, X2 OH, or X1 and X2 together are O, OS(O)O or OS(O2)O. The compound of formula (III) can be a single enantiomer or a mixture of enantiomers and/or diastereomers.
In a further aspect, the present invention provides a compound having the formula (III): 
wherein R1 is hydrogen, fluorine, chlorine or SiR5R6R7, wherein R5, R6, and R7 are independently the same or different an alkyl group or an aryl group, R2 is an alkyl group, R3 is a protecting group, R4 is an alkyl group, an allyl group, a propargyl group or a benzyl group, R8 is xe2x80x94CHO, xe2x80x94CH2OH, xe2x80x94CH2OR9, wherein R9 is a protecting group, and X1 is OH, X2 is H or OH, or X1 and X2 together are O, OS(O)O or OS(O2)O.
In a further aspect, the present invention provides a compound having the formula (VI): 
wherein R1 is, for example, hydrogen, fluorine, chlorine or SiR5R6R7 wherein R5, R6, and R7 are independently the same or different an alkyl group (preferably a lower alkyl group) or an aryl group. R2 is an alkyl group (preferably, a lower alkyl group). R3 is a protecting group (for example, acetate, methoxymethyl or tert-butyldimethylsilyl). R4 is an alkyl group (preferably, a lower alkyl group), an allyl group, a propargyl group or a benzyl group. Preferred embodiments of the compound of formula (VI) for use in the synthetic methods of the present invention include those in which R1 is H or a trimethylsilyl group, R2 is a lower alkyl group, and R4 is an ethyl group.
In still another aspect, the present invention provides a compound having the formula (VII): 
wherein R1 is, for example, hydrogen, fluorine, chlorine or SiR5R6R7 wherein R5, R6, and R7 are independently the same or different an alkyl group (preferably a lower alkyl group) or an aryl group. R2 is an alkyl group (preferably, a lower alkyl group). R3 is a protecting group (for example, acetate, methoxymethyl or tert-butyldimethylsilyl). R4 is an alkyl group (preferably, a lower alkyl group), an allyl group, a propargyl group or a benzyl group. In the compounds of formula (VII), X1 is OH, X3 is OH, or together X1 and X3 are O, OS(O)O or OS(O2)O. The compound of formula (VII) can be a single enantiomer or a mixture of enantiomers and/or diastereomers. Preferred embodiments of the compound of formula (VII) for use in the synthetic methods of the present invention include those in which R1 is H or a trimethylsilyl group, R2 is a lower alkyl group, and R4 is an ethyl group.
Reaction procedures such as the Wittig reaction, the Stille reaction, the Sharpless asymmetric epoxidation reaction, the Sharpless asymmetric dihydroxylation reaction, and the Jacobsen-Katsuki epoxidation reaction used in the present invention are well known in the art. Stille reactions are described, for example, in Farina, V., et al., Org. React. (N.Y.), 50, 1, (1997), the disclosure of which is incorporated herein by reference. Sharpless epoxidation reactions are described in A. Pfenniger, Synthesis, 89 (1986);. Katsuki, T. and Martin, V. S., Org. React. (N.Y.), 48, 1, (1996), the disclosures of which are incorporated herein by reference. Sharpless asymmetric dihydroxylation reactions are described, for example, in Kolb, H. C., et al., Chem. Rev., 94, 2483, (1994), the disclosure of which is incorporated herein by reference. Jacobsen-Katsuki epoxidation reactions are described, for example, in Jacobsen, E. N., Comprehensive Organometallic Chemistry II: A Review of the Literature 1982-1994; Abel, E. W., et al., Pergamon: Oxford, UK,; Vol. 12; pp 1097 (1995), Linker, T., Angew. Chem., Int. Ed. Engl., 36, 2060 (1997), the disclosures of which are incorporated herein by reference.
In general, the Wittig reaction is the coupling of a phosphorous ylide or a related species (for example, a phosphate or phosphonate anion) with an aldehyde or ketone to make an alkene. The Peterson olefination is the coupling of an xcex1-silyl anion with an aldehyde or ketone to provide an alkene. This reaction may occur in one step, but a two step procedure through the intermediacy of a xcex2-hydroxysilane is also common. This intermediate yields an alkene on treatment with acid or base.
The Stille reaction is the coupling of an organostannane and an organic halide (chloride, bromide or iodide) in the presence of a transition metal (often palladium) and a ligand (often a phosphine). The stannane is typically an aryltrialkylstannane, an alkenyltrialkylstannane or an acyltrialkylstannane and the aryl, alkenyl or acyl group is preferentially coupled. The halide is often an aryl halide or an alkenyl halide.
The Sharpless epoxidation is the conversion of an alkene to an enantiomerically enriched epoxide by treatment with a titanium compound (for example titanium tetraisopropoxide) in the presence of tartrate derivatives (for example, diethyl tartrate) and an oxidant (for example, tert-butyl hydroperoxide). Other compounds and additives are sometimes used to accelerate the reaction or increase the ee.
The Sharpless asymmetric dihydroxylation (SAD or sometimes AD) is the conversion of an alkene to an enantiomerically enriched 1,2-diol by treatment with an osmium compound (for example, potassium osmate or osmium tetraoxide) in the presence of one of many ligands derived from the quinine family of alkaloids, and oxidant (for example, tert-butyl hydroperoxide or potassium ferricyamide) and (optionally) other additives (for example, methane sulfonamide) to accelerate the reaction and/or increase the ee. Complete commercial preparations of reagents for the Sharpless epoxidation are available under the xe2x80x9cAD-MIXxe2x80x9d name, but many other ligands, oxidants and additives are also readily available.
The Jacobsen-Katsuki (or sometimes Jacobsen) epoxidation is the conversion of an alkene to an enantiomerically enriched epoxide by treatment with a manganese complex bearing, for example, a chiral SALEN ligand, in the presence of an oxidant and (optionally) other additives to accelerate the reaction and increase the ee.